Atherosclerotic coronary artery disease (CAD) is the leading cause of death in the developed world. Progression of CAD is highly variable and is governed by both environmental factors and genetic determinants. We have known for some time that the contribution of genetics to CAD is at least equal to that of environmental risk factors. The genetic risk is thought to be due to an unfavorable combination of genetic variations in multiple genes; but the genes that control this variability in susceptibility to disease are not well characterized. The study of complex genetic diseases like CAD has proven to be a tremendous challenge. The most efficient approach to identifying susceptibility genes involves looking for correlation between a specific allele and disease in cases and controls (association design). Until recently, association studies were restricted to a "candidate gene" approach where variants, typically single nucleotide changes or polymorphisms (also called SNPs) in genes are evaluated on a gene by gene basis. While an important first step, candidate gene studies are limited by pre-defined hypotheses. A complementary approach is to use a more comprehensive and unbiased approach to look at variation in all genes in the genome through a Whole Genome Association (WGA) study. To identify allelic variation that is associated with CAD and other clinically relevant phenotypes, we initiated the ADVANCE study (Atherosclerotic Disease, VAscularfunctioN, and genetiC Epidemiology). ADVANCE is a large, multi-ethnic, population-based case control study of patients receiving care in Kaiser Permanente of Northern California. We will perform a high density WGA scan using over 500,000 SNPs on a population of highly selected and characterized cohort of young individuals with premature CAD from ADVANCE. To validate positive associations from the WGA scan, we will perform targeted regional genotyping in a cohort of older individuals with clinically significant CAD and a similar group of control subjects as well as replication in the independent INTERHEART study. The identification of CAD susceptibility genes is potentially of tremendous value to public health because these efforts could change our ability to both diagnose and treat CAD. [unreadable] [unreadable] [unreadable]